Aromatase (also known as CYP19) is a member of the general class of cytochrome P450 enzymes. It catalyzes the conversion of 19-methyl androgens to estrogens, which is a crucial step in the biosynthesis of estrogens in the human body (Ghosh, D., et al., Nature 2009, 457, 219-223). Aromatase inhibitors (AIs) have been widely used for treatment of hormone receptor-positive breast cancer in postmenopausal women. Currently, three AIs, letrozole (1), anastrozole (2) and exemestane (3) (FIG. 1), have been approved by the FDA. Comparative clinical trials have demonstrated that AIs are superior to the selective estrogen receptor modulator (SERM) tamoxifen (4) (FIG. 1) in the treatment of postmenopausal women with breast cancer (Thurlimann, B. et al., N. Engl. J. Med. 2005, 353, 2747-2757; Williams, N., Lancet Oncol. 2008, 9, 45-53). In the five-year ATAC trial, the use of anastrozole resulted in a 13% improvement of disease-free survival, 21% reduction in the rate of recurrence, 42% reduction in occurrence of contralateral breast cancer and 16% reduction in risk of distant metastasis when compared to tamoxifen (Howell, A. et al., Lancet 2005, 365, 60-62).
Even though the use of AIs is reported to cause fewer vaginal bleeding events, thromboembolic event, and endometrial cancer occurrences than tamoxifen, AIs are associated with other side effects, such as severe musculoskeletal pain, reduction of bone density, and an increased frequency of bone fractures and cardiovascular events due to the non-selective depletion of estrogen in the whole body (Heshmati, H. M. et al., J. Bone Miner. Res. 2002, 17, 172-178; Bundred, N., Br. J. Cancer 2005, 93, S23-S27). According to the five-year ATAC trial, anastrozole treatment led to a significantly higher incidence of bone fractures (11% vs. 7.7%) and arthralgia (35.6% vs 29.4%) than tamoxifen. Meanwhile, the increased musculoskeletal pain caused by AIs negatively impacts patient compliance. More than 10% of the patients discontinue AI therapy because of musculoskeletal toxicity after 6 months. Non-adherence rates are higher, since only 62-79% of women adhere (take more than 80% of the prescribed dose) after three years (Henry, N. L. et al., Breast Cancer Res. Treat. 2008, 111, 365-372).
Therefore further improvement in this class of therapeutic agents is highly anticipated in order to reduce the current AI therapies' side effects, including severe musculoskeletal pain, reduction of bone density, increased frequency of bone fractures, and others.